The present invention relates to delta-opioid receptor agonists/antagonists. More particularly, the present invention relates to 4-[aryl(piperidin-4-yl)]aminobenzamides which are delta-opioid receptor agonists useful as analgesics.
WO9723466 to Plobeck N. et al., discloses compounds (approximately) of the formula: 
which are mu-opioid antagonists.
WO9636620 to Dondio G., discloses compounds (most relevantly) of the formula: 
which are delta-opioid agonists/antagonists.
WO9710230 to Dondio G. et al., discloses compounds (most relevantly) of the formula: 
which are delta-opioid, kappa-opioid and mu-opioid receptor agonists/antagonists.
WO9315062 to Chang K. et al., discloses compounds (approximately) of the formula: 
which are delta-opioid and mu-opioid receptor agonists.
It is an object of the present invention to provide delta-opioid receptor agonists as analgesics.
It is another object of the present invention to provide delta-opioid receptor selective agonists as analgesics having reduced side-effects.
It is another object of the present invention to provide delta-opioid receptor agonists/antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.
It is another object of the present invention to provide delta-opioid receptor selective agonists/antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases, having reduced side-effects.
There are provided by the present invention delta-opioid receptor agonists/antagonists of the general formula: 
where
Ar is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 1 to 3 R7;
R1 and R2 are independently selected from the group consisting of hydrogen, C1-8alkyl; phenyl, optionally mono-, di-, or tri-substituted with halo, C1-6alkyl, C1-6alkoxy or trifluoromethyl; or benzyl, optionally mono-, di-, or tri-substituted with halo, C1-6alkyl, C1-6alkoxy or trifluoromethyl, or alternatively, R1 and R2 are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and hexamethyleneiminyl, each said ring optionally substituted with 1 to 4 methyl groups;
R3, R4 and R5 are independently selected from hydrogen and C1-4alkyl;
R6 is selected from the group consisting of hydrogen; C1-8alkyl; C3-6cycloalkylC1-3alkyl, C3-6alkenyl; C1-6alkoxyC1-3alkyl; 4-C1-4alkyl-4,5-dihydro-5-oxo-1H-tretrazol-1-ylC1-4alkyl; thien-2-ylC1-4alkyl; thien-3-ylC1-4alkyl; furan-2-ylC1-4alkyl; furan-3-ylC1-4alkyl; pyrrol-2-ylC1-4alkyl; pyrrol-3-ylC1-4alkyl; pyridin-2-ylC1-4alkyl; pyridin-3-ylC1-4alkyl; pyridin-4-ylC1-4alkyl; pyrazinylC1-4alkyl; pyrimidin-2-ylC1-4alkyl; pyrimidin-4-ylC1-4alkyl; pyrimidin-5-ylC1-4alkyl; thiazol-2-ylC1-4alkyl; thiazol-4-ylC1-4alkyl; thiazol-5-ylC1-4alkyl; oxazol-2-ylC1-4alkyl oxazol-4-ylC1-4alkyl; oxazol-5-ylC1-4alkyl and phenylC1-4alkyl, where the foregoing thienyl, furanyl, pyrrolyl, thiazolyl and oxazolyl are optionlly mono-, di-, or tri-substituted with a non-fused R7 and the foregoing pyridinyl, pyrazinyl, pyrimidinyl and phenyl is optionally mono-, di-, or tri-substituted with R7;
R7 is independently selected from the group consisting of hydroxy, halo, C1-3alkyl, C1-3alkoxy, C1-3acyl, C1-3acyloxy, cyano, amino, C1-3acylamino, C1-3alkylamino, di(C1-3alkyl)amino, C1-3alkylthio, C1-3alkylsulfonyl, trifluoromethyl and trifluoromethoxy, and two R7 can together form a single fused moiety selected from the group consisting of xe2x80x94(CH2)3-5xe2x80x94 and xe2x80x94O(CH2)1-3Oxe2x80x94 attached to adjacent carbon atoms of Ar; and
R8 is independently selected from the group consisting of halo, C1-6alkyl, C1-6alkoxy and trifluoromethyl.
As delta-opioid receptor agonists, such compounds are useful as analgesics. Depending on their agonist/antagonist effect, such compounds may also be useful immunosuppressants, antiiinflammantory agents, agents for treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.
The core structure of the compounds of the present invention can be made in a two step process. This process must be modified as required by the strategy employed to obtain the various substituents. In a first strategy, the starting materials are substituted as desired with the final substituents and, where the substituents or their protected forms are stable to the reaction conditions, the core structure may be subsequently made by the two step process. In a second strategy, the final core structure is obtained and, where the core structure is stable to the modifying reaction conditions, the substituents are modified as desired. Variations might include modifying the substituents on intermdiates or replacing precursor substituents on the finished core structure.
Scheme A generally describes the manufacture of the compounds of the present invention. The first step of Scheme A is a reductive alkylation of piperidone A1 and amine A2 to produce N-aryl-piperidineamine A3. The reductive alkylation is carried out by combining the ketone A1, amine A2, and an appropriate solvent/reducing agent combination to form a reaction mixture which is cooled or heated as necessary. Suitable solvent/reducing agent combinations include 1,2-dichloroethane or acetonitrile/NaBH(OAc)3+acid catalyst; methanol/NaBH3CN+acid catalyst; methanol or ethanol or isopropanol/NaBH4; or alcoholic solvent/H2+noble metal catalyst. The use of the 1,2-dichloroethane or acetonitrile/NaBH(OAc)3+acid catalyst combination is further described by Abdel-Magid, A. F., et al., J. Org.Chem., Vol. 61, pp 3849-3862 (1996). In the second step of Scheme A, the N-aryl-piperidineamine A3 is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide A4 in the presence of a palladium catalyst, phosphine ligand and base to give the (N-aryl, N-piperidin-4-yl)aminobenzamide. Preferred palladium catalysts include PdCl2+phosphine ligand, tris(dibenzylideneacetone)dipalladium(0) which is Pd2(dba)3+phosphine ligand, Pd(OAc)2+phosphine ligand and Pd(Ph3P)4(0). Suitable phosphine ligands include BINAP and tri(o-tolyl phosphine). Suitable bases include NaOtBu and Cs2CO3. The reaction of the second step is an arylation further described by Buchwald, S. L., J. Org. Chem., Vol. 61, p 1133 (1996). The manufacture of the various starting materials for Scheme A is well within the skill of persons versed in this art. 
Preferred Ar is phenyl.
Preferred R1 and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, p-trifluoromethylphenyl, benzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl and p-trifluoromethylbenzyl, or alternatively, preferred R1 and R2 are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl and piperidinyl.
Preferred R3, R4 and R5 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl and t-butyl.
Preferred R6 are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropylmethyl, ethenyl, allyl, methoxymethyl, benzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl, p-trifluoromethylbenzyl, p-aminobenzyl, thien-2-ylCH2CH2xe2x80x94, thien-3-ylCH2CH2xe2x80x94, pyridin-3-ylCH2CH2xe2x80x94, pyridin-4-ylCH2CH2xe2x80x94, thiazol-2-ylCH2CH2xe2x80x94 and phenylCH2CH2xe2x80x94, any of which may be R7 substituted as taught above. It is a preferred embodiment of R6, that where it contains a phenyl or heteroaromatic group, that the moiety linking the phenyl or heteroaromatic group to the piperidinyl moiety be at least two carbon atoms long. Thus this linking moiety might be ethyl or propyl which is beta substituted with the phenyl or heteroaromatic group, or propyl, which is gamma substituted.
Preferred R7 are independently selected from the group consisting of hydroxy, chloro, bromo, fluoro, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, formyl, acyl, acetoxy, cyano, amino, methylamido, methylamino, N,N-dimethylamino, methylthio, methylsulfonyl, trifluoromethoxy and trifluoromethyl, and preferred moieties where two R7 together form a single moiety are selected from the group consisting of propylene, butylene and xe2x80x94OCH2Oxe2x80x94.
Preferred R8 are independently selected from the group consisting of chloro, bromo, fluoro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy and trifluoromethyl.
Preferred compounds of the present invention have the general structure: 
where R1, R2, R3, R6 and R7 are dependently selected from the groups consisting of:
The compounds of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals, such as, humans by administration of an analgesically effective dose. The dosage range would be from about 1 to 3000 mg, in particular about 10 to 1000 mg or about 25 to 500 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated. In regards to the use of these compounds as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases, a therapeutically effective dose can be determined by persons skilled in the art by use of established animal models. Such dosage would likely fall in the range of from about 1 to 3000 mg of active ingredient 1 to 4 times per day for an average (70 kg) human. Pharmaceutical compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the invention or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., table, capsule, powder, injection, teaspoonful and the like, and amount of the active ingredient necessary to deliver and effective dose as described above.
The pharmaceutically acceptable salts referred to above generally take a form in which the nitrogen of the piperidinyl ring is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic or saccharic.